Angiopoietin is part of a family of vascular growth factors that play a role in embryonic and postnatal angiogenesis. Ang1 promotes migration of endothelial and some non-endothelial cells such as smooth muscle cells. Ang1 also induces sprouting and reorganisation of endothelial cells into tubules. Ang1 exerts potent anti-inflammatory effects on endothelial cells, suppressing Vascular Endothelial Growth Factor (VEGF) induced upregulation of E-selectin, ICAM-1 and VCAM-1, and inhibiting leucocyte adhesion and transmigration in response to VEGF and TNF-α (Kim et al. 2001a).
Many studies have shown that overexpression of Ang1, or the addition of supplemental Ang1, leads to beneficial effects in relieving ischemia and restoring the function of several organs, including limbs, brain, articular joints, kidneys and most significantly, in the heart. Other beneficial effects include reliving thrombosis (Kim et al. 2001b). Accordingly, Ang1 exhibits a number of key properties that would suggest its utility as a therapeutic for cardiovascular disease.
Amongst the cascade of growth factors required for the development of a functional vascular system, Ang1 and VEGF fulfil central roles. Accordingly, for therapeutic vascularization in the treatment of ischemic myocardium the use of Ang1 in combination with VEGF is also viewed as a highly promising candidate.
Previously, the combined administration of Ang1 and VEGF-A into myocardial infract or peri-infarct zones in test animals has been shown to increase neovascularization and reduce myocardial apoptosis, leading to increased cardiomyocyte regeneration at the injection sites, as well as improved vascular perfusion and cardiac function. Submaximal doses of Ang1 and VEGF at a ratio of about 20:1 enhanced these effects and was more potent than that of either factor alone (Chae et al. 2000). These results show that combined treatment of Ang1 and VEGF could be used to produce therapeutic vascularization.
Recently, stem cell therapy has emerged as one of the potential treatments for ischemic heart disease (Huang et al. 2011; Lijie et al. 2007).
The use of stem cells alone to promote angiogeneisis remains limited because of insufficient expression of angiogenic factors in many types of stem cells. Genetic modification of stem cells, involving transfection of stem cells with a nucleic acid molecule encoding Ang1, has been employed to address this limitation. The use of genetically modified stem cells has its drawbacks, however, due to complexities with the technology and potentially undesirable effects caused by the genetic modification process.